CN104262205A - N-acryl biguanide hydriodate compound as well as preparation method and application thereof - Google Patents
N-acryl biguanide hydriodate compound as well as preparation method and application thereof Download PDFInfo
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- 0 CC1=CC=CC(NC(N)=NC(N(*)*)=N)=C*1 Chemical compound CC1=CC=CC(NC(N)=NC(N(*)*)=N)=C*1 0.000 description 4
- IDAKXZKKMPSXHU-UHFFFAOYSA-N CN(C)C(/N=C(\N)/Nc(cc1)ccc1[N+]([O-])=O)=N Chemical compound CN(C)C(/N=C(\N)/Nc(cc1)ccc1[N+]([O-])=O)=N IDAKXZKKMPSXHU-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses an N-acryl biguanide hydriodate compound, shown in a formula (III) in the specification. A preparation method of the N-acryl biguanide hydriodate compound comprises the following steps: mixing biguanide hydrochloride shown in a formula (I) in the specification and an aromatic iodide shown in a formula (II) in the specification in a solvent, stirring to carry out reaction for 2-20h at temperature of 60-100 DEG C under the catalysis of a metallic copper catalyst and in the presence of a ligand and an alkaline matter, and after reaction, carrying out aftertreatment on a reaction solution to obtain the N-acryl biguanide hydriodate compound shown in the formula (III). The N-acryl biguanide hydriodate compound shown in the formula (III) can be applied to preparing a medicament for treating a placental villi cancer.
Description
(1) technical field
The present invention relates to a kind of new N-aryl biguanides hydriodate compounds and preparation method thereof, and the application in preparation treatment placental villi cancer drug.
(2) background technology
Biguanide compound is the important nitrogenous compound of a class, has biological activity widely, comprises hyperglycemia activity, anti-tumor activity, antibacterial activity etc.And less to the research of Biguanide derivative report, mainly comprise and react by N1,N1-Dimethylbiguanide and halogenated aliphatic hydrocarbon or disulfide, synthesize the biguanide compound of N-alkyl and the replacement of N-alkylthio.Therefore, the biguanide compound that preparation is novel is also studied its antineoplastic activity and is had important theory significance and actual application value.
(3) summary of the invention
The present invention adopts following technical scheme:
A kind of such as formula the N-aryl biguanides hydriodate compounds shown in (III):
In formula (III): R
1, R
2respective is independently hydrogen, C1 ~ C10 alkyl or C6 ~ C10 aryl, or R
1, R
2n is between the two combined to form the heterocycle containing N or the C4 ~ C8 containing N, O; Preferred R
1, R
2respective is independently hydrogen, methyl or phenyl, or R
1, R
2n is between the two combined to form Pyrrolidine ring, piperidine ring or morpholine ring; R
3represent a substituting group on hydrogen or phenyl ring, described substituting group is selected from C1 ~ C10 alkyl, C1 ~ C10 alkoxyl group, C6 ~ C10 aryl, halogen, nitrogenous electron-withdrawing substituent or alkylsulfonyl, preferred R
3represent a substituting group on hydrogen or phenyl ring, described substituting group is selected from methyl, methoxyl group, oxyethyl group, phenyl, cyano group, nitro, fluorine, chlorine, bromine or N-sulfonyl pyrrole acyl group;
Present invention also offers the preparation method of the N-aryl biguanides hydriodate compounds shown in a kind of formula (III), described preparation method is:
Being mixed with the fragrant iodo thing shown in formula (II) by biguanide hydrochloride shown in formula (I) adds in solvent, under the katalysis of metallic copper catalyzer, and under the existence of part and alkaline matter, in 60 ~ 100 DEG C of stirring reaction 2 ~ 20h, after reaction terminates, reaction solution obtains N-aryl biguanides hydriodate compounds shown in formula (III) through aftertreatment.
Described solvent is water, alcohols, ethers, sulfoxide type or nitrile; Described metallic copper catalyzer is copper halide or cuprous halide; Described part is aromatic nitrogen heterocycle, fatty nitrogen heterocyclic or amino acid; Described alkaline matter is mineral alkali or organic bases; The amount of substance of biguanide hydrochloride, metallic copper catalyzer, part, alkaline matter shown in fragrant iodo thing and formula (I) shown in described formula (II) is than being 1:0.7 ~ 1.3:0.05 ~ 0.15:0.1 ~ 0.3:3 ~ 9;
In formula (I): R
1, R
2respective is independently hydrogen, C1 ~ C10 alkyl or C6 ~ C10 aryl, or R
1, R
2n is between the two combined to form the heterocycle containing N or the C4 ~ C8 containing N, O; Preferred R
1, R
2respective is independently hydrogen, methyl or phenyl, or R
1, R
2n is between the two combined to form Pyrrolidine ring, piperidine ring or morpholine ring;
In formula (II): R
3represent a substituting group on hydrogen or phenyl ring, described substituting group is selected from C1 ~ C10 alkyl, C1 ~ C10 alkoxyl group, C6 ~ C10 aryl, halogen, nitrogenous electron-withdrawing substituent or alkylsulfonyl; Preferred R
3represent a substituting group on hydrogen or phenyl ring, described substituting group is selected from methyl, methoxyl group, oxyethyl group, phenyl, cyano group, nitro, fluorine, chlorine, bromine or N-sulfonyl pyrrole acyl group.
Preparation method of the present invention, preferably described solvent is water, ethanol, Virahol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile, DMF or dimethyl sulfoxide (DMSO), is particularly preferably tetrahydrofuran (THF); The volumetric usage of usual described solvent counts 10 ~ 50mL/g with the quality of biguanide hydrochloride formula (I) Suo Shi.
Preferably described metallic copper catalyzer is cuprous chloride, cuprous bromide, cuprous iodide or cupric chloride, is particularly preferably cuprous iodide.
Preferably described part is 2, and 2 '-dipyridyl, 1,10-phenanthroline, triethylene diamine, glycine, Methionin, L-glutamic acid, Gelucystine, L-Ala, aspartic acid, Threonine or α-amino-isovaleric acid, be particularly preferably 2,2 '-dipyridyl.
Preferably described alkaline matter is salt of wormwood, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassiumphosphate or triethylamine, is particularly preferably potassiumphosphate.
In preparation method of the present invention, described aftertreatment can be adopted with the following method: after reaction terminates, reacting liquid filtering, filter residue methanol wash, concentrated filtrate, column chromatography (methylene dichloride: methyl alcohol=8:1, V:V), the elutriant containing target compound is collected, underpressure distillation, drying obtains target compound (III)
The invention still further relates to the anti-tumor activity of described N-aryl biguanides hydriodate compounds, and the application in preparation treatment placental villi cancer drug.
Beneficial effect of the present invention is mainly reflected in: the new preparation method of (1) N-aryl biguanides hydriodate compounds, this technological reaction mild condition, easy to operate, cost is low, has prospects for commercial application widely.(2) N-aryl biguanides hydriodate compounds provided by the present invention demonstrates certain anti-human placental villi cancer activity, for new medicament screen and exploitation are laid a good foundation, has good practical value.
(4) embodiment
Below will the present invention is further illustrated by embodiment, but protection scope of the present invention is not limited thereto.
Embodiment 1: the preparation of compound (III-1)
Metformin (0.165g, 1.0mmol) is added, to methoxyl group iodobenzene (0.243g in reaction vessel, 1.0mmol), cuprous iodide (0.0190g, 0.10mmol), 2,2 '-dipyridyl (0.0312g, 0.20mmol), potassiumphosphate (1.3g, 6.0mmol), mixing in tetrahydrofuran (THF) (5mL), stirring reaction 12 hours in 80 DEG C of oil baths; After reaction terminates, filter, filter residue methanol wash, concentrated filtrate, column chromatography (methylene dichloride: methyl alcohol=8:1, V:V), collect R
fthe elutriant of value 0.3 ~ 0.35, underpressure distillation, drying obtains target compound (III-1) 0.352g, and yield is 97%.
1H?NMR(500?MHz,DMSO-d
6)δ8.83(s,1H),7.46(s,2H),7.24(d,J＝9.0?Hz,2H),6.89(d,J＝9.0?Hz,2H),6.62(s,2H),3.73(s,3H),2.94(s,6H).
Embodiment 2:
Cuprous iodide is changed into cuprous chloride (0.0099g, 0.10mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.131g, yield is 36%.
Embodiment 3:
Cuprous iodide is changed into cuprous bromide (0.0143g, 0.10mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.189g, yield is 52%.
Embodiment 4:
Cuprous iodide is changed into cupric chloride (0.134g, 0.10mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.0617g, yield is 17%.
Embodiment 5:
Change solvents tetrahydrofurane into acetonitrile, other operations are with embodiment 1, and obtain target compound (III-1) 0.254g, yield is 70%.
Embodiment 6:
Change solvents tetrahydrofurane into Isosorbide-5-Nitrae-dioxane, other operations are with embodiment 1, and obtain target compound (III-1) 0.236g, yield is 65%.
Embodiment 7:
Change solvents tetrahydrofurane into water, other operations are with embodiment 1, and obtain target compound (III-1) 0.0254g, yield is 7%.
Embodiment 8:
Change solvents tetrahydrofurane into DMF, other operations are with embodiment 1, and obtain target compound (III-1) 0.153g, yield is 42%.
Embodiment 9:
Change solvents tetrahydrofurane into ethanol, other operations are with embodiment 1, and obtain target compound (III-1) 0.116g, yield is 32%.
Embodiment 10:
Change solvents tetrahydrofurane into Virahol, other operations are with embodiment 1, and obtain target compound (III-1) 0.222g, yield is 61%.
Embodiment 11:
Change solvents tetrahydrofurane into dimethyl sulfoxide (DMSO), other operations are with embodiment 1, and obtain target compound (III-1) 0.174g, yield is 48%.
Embodiment 12:
2,2 '-dipyridyl is changed into 1,10-phenanthroline (0.036g, 0.20mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.145g, yield is 41%.
Embodiment 13:
2,2 '-dipyridyl is changed into triethylene diamine (0.022g, 0.20mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.240g, yield is 66%.
Embodiment 14:
2,2 '-dipyridyl is changed into glycine (0.015g, 0.20mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.262g, yield is 72%.
Embodiment 15:
2,2 '-dipyridyl is changed into Methionin (0.029g, 0.20mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.276g, yield is 76%.
Embodiment 16:
2,2 '-dipyridyl is changed into L-glutamic acid (0.029g, 0.20mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.272g, yield is 75%.
Embodiment 17:
2,2 '-dipyridyl is changed into Gelucystine (0.048g, 0.20mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.254g, yield is 70%.
Embodiment 18:
2,2 '-dipyridyl is changed into L-Ala (0.018g, 0.20mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.301g, yield is 83%.
Embodiment 19:
2,2 '-dipyridyl is changed into aspartic acid (0.027g, 0.20mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.251g, yield is 69%.
Embodiment 20:
2,2 '-dipyridyl is changed into Threonine (0.024g, 0.20mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.258g, yield is 71%.
Embodiment 21:
2,2 '-dipyridyl is changed into α-amino-isovaleric acid (0.023g, 0.20mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.229g, yield is 63%.
Embodiment 22:
Potassiumphosphate is changed into salt of wormwood (0.829g, 6.0mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.051g, yield is 14%.
Embodiment 23:
Potassiumphosphate is changed into sodium carbonate (0.636g, 6.0mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.058g, yield is 16%.
Embodiment 24:
Potassiumphosphate is changed into cesium carbonate (1.955g, 6.0mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.258g, yield is 71%.
Embodiment 25:
Potassiumphosphate is changed into sodium hydroxide (0.240g, 6.0mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.094g, yield is 26%.
Embodiment 26:
Potassiumphosphate is changed into potassium hydroxide (0.337g, 6.0mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.109g, yield is 30%.
Embodiment 27:
Potassiumphosphate is changed into triethylamine (0.607g, 6.0mmol), other operations are with embodiment 1, and obtain target compound (III-1) 0.011g, yield is 3%.
Embodiment 28:
Temperature of reaction is reduced to 60 DEG C, other operations are with embodiment 1, and obtain target compound (III-1) 0.127g, yield is 35%.
Embodiment 29:
Temperature of reaction is elevated to 100 DEG C, other operations are with embodiment 1, and obtain target compound (III-1) 0.301g, yield is 83%.
Embodiment 30:
Change the amount of cuprous iodide into 0.010g, 0.05mmol, other operations are with embodiment 1, and obtain target compound (III-1) 0.149g, yield is 41%.
Embodiment 31:
Change the amount of cuprous iodide into 0.029g, 0.15mmol, other operations are with embodiment 1, and obtain target compound (III-1) 0.222g, yield is 61%.
Embodiment 32:
Change the amount of Metformin into 0.215g, 1.3mmol, other operations are with embodiment 1, and obtain target compound (III-1) 0.240g, yield is 66%.
Embodiment 33:
Change the amount of Metformin into 0.116g, 0.7mmol, other operations are with embodiment 1, and obtain target compound (III-1) 0.320g, yield is 88%.
Embodiment 34:
Change the amount of 2,2 '-dipyridyl into 0.0156g, 0.1mmol, other operations are with embodiment 1, and obtain target compound (III-1) 0.232g, yield is 64%.
Embodiment 35:
Change the amount of 2,2 '-dipyridyl into 0.047g, 0.3mmol, other operations are with embodiment 1, and obtain target compound (III-1) 0.272g, yield is 75%.
Embodiment 36:
Change the amount of potassiumphosphate into 0.637g, 3mmol, other operations are with embodiment 1, and obtain target compound (III-1) 0.174g, yield is 48%.
Embodiment 37:
Change the amount of potassiumphosphate into 1.910g, 9mmol, other operations are with embodiment 1, and obtain target compound (III-1) 0.309g, yield is 85%.
Embodiment 38: the preparation of compound (III-2)
Operation, with embodiment 1, just will change into oxyethyl group iodobenzene (0.248g, 1mmol) to methoxyl group iodobenzene, and obtained target compound (III-2) 0.240g, yield is 62%.
1H?NMR(500?MHz,DMSO-d
6)δ8.80(s,1H),7.43(s,2H),7.22(d,J＝8.4?Hz,2H),6.87(d,J＝8.4?Hz,2H),6.59(s,2H),3.98(d,J＝6.5?Hz,2H),2.94(s,6H),1.30(t,J＝6.5?Hz,3H).
Embodiment 39: the preparation of compound (III-3)
Operation, with embodiment 1, just will change into methyl iodobenzene (0.217g, 1mmol) to methoxyl group iodobenzene,
Obtained target compound (III-3) 0.3g, yield is 87%.
1H?NMR(500?MHz,DMSO-d
6)δ8.88(s,1H),7.51(s,2H),7.22(d,J＝8.2?Hz,2H),7.11(d,J＝8.2?Hz,2H),6.61(s,2H),2.95(s,6H),2.25(s,3H).
Embodiment 40: the preparation of compound (III-4)
Operation, with embodiment 1, just will change 3-methyl iodobenzene (0.217g, 1mmol) into methoxyl group iodobenzene, and obtained target compound (III-4) 0.273g, yield is 78%.
1H?NMR(500?MHz,DMSO-d
6)δ8.90(s,1H),7.54(s,2H),7.14-7.19(m,3H),6.83-6.90(m,1H),6.63(s,2H),2.96(s,6H),2.26(s,3H).
Embodiment 41: the preparation of compound (III-5)
Operation, with embodiment 1, just will change 2-methyl iodobenzene (0.217g, 1mmol) into methoxyl group iodobenzene, and obtained target compound (III-5) 0.123g, yield is 34%.
1H?NMR(500?MHz,DMSO-d
6)δ8.38(s,1H),7.40(s,2H),7.07-7.39(m,4H),6.73(s,2H),2.91(s,6H),2.45(s,3H).
Embodiment 42: the preparation of compound (III-6)
Operation, with embodiment 1, just will change 2-phenyl iodobenzene (0.280g, 1mmol) into methoxyl group iodobenzene, and obtained target compound (III-6) 0.307g, yield is 75%.
1H?NMR(500?MHz,DMSO-d
6)δ9.09(s,1H),7.60-7.66(m,6H),7.30-7.48(m,5H),6.69(s,2H),2.98(s,6H).
Embodiment 43: the preparation of compound (III-7)
Operation, with embodiment 1, just will change iodobenzene (0.204g, 1mmol) into methoxyl group iodobenzene, and obtained target compound (III-7) 0.289g, yield is 86%.
1H?NMR(500?MHz,DMSO-d
6)δ8.97(s,1H),7.57(s,2H),7.39-7.21(m,4H),7.05(t,J＝7.3?Hz,1H),6.64(s,2H),2.96(s,6H).
Embodiment 44: the preparation of compound (III-8)
Operation, with embodiment 1, just will change into fluorine iodobenzene (0.223g, 1mmol) to methoxyl group iodobenzene, and obtained target compound (III-8) 0.255g, yield is 73%.
1H?NMR(500?MHz,DMSO-d
6)δ8.98(s,1H),7.54(s,2H),7.34-7.37(m,2H),7.11-7.15(m,2H),6.64(s,2H),2.95(s,6H).
Embodiment 45: the preparation of compound (III-9)
Operation, with embodiment 1, just will change into chloroiodobenzone (0.238g, 1mmol) to methoxyl group iodobenzene, and obtained target compound (III-9) 0.3g, yield is 82%.
1H?NMR(500?MHz,DMSO-d
6)δ9.07(s,1H),7.63(s,2H),7.39(d,J＝8.8,2H),7.35(d,J＝8.8,2H),6.67(s,2H),2.96(s,6H).
Embodiment 46: the preparation of compound (III-10)
Operation, with embodiment 1, just will change into bromo-iodobenzene (0.283g, 1mmol) to methoxyl group iodobenzene, and obtained target compound (III-10) 0.282g, yield is 68%.
1H?NMR(500?MHz,DMSO-d
6)δ9.11(s,1H),7.64(s,2H),7.47(d,J＝8.5?Hz,2H),7.34(d,J＝8.5?Hz,2H),6.69(s,2H),2.96(s,6H)
Embodiment 47: the preparation of compound (III-11)
Operation, with embodiment 1, just will change 3-chloroiodobenzone (0.238g, 1mmol) into methoxyl group iodobenzene, and obtained target compound (III-11) 0.299g, yield is 82%.
1H?NMR(500?MHz,DMSO-d
6)δ9.12(s,1H),7.68(s,2H),7.57(s,1H),7.29-7.34(m,1H),7.24(d,J＝8.0Hz,2H),7.08(d,J＝8.0Hz,1H),6.70(s,2H),2.92(s,6H).
Embodiment 48: the preparation of compound (III-12)
Operation, with embodiment 1, just will change into itrile group iodobenzene (0.229g, 1mmol) to methoxyl group iodobenzene, and obtained target compound (III-12) 0.339g, yield is 94%.
1H?NMR(500?MHz,DMSO-d
6)δ9.41(s,1H),7.79(s,2H),7.74(d,J＝8.7?Hz,2H),7.58(d,J＝8.7?Hz,2H),6.78(s,2H),2.98(s,6H).
Embodiment 49: the preparation of compound (III-13)
Operation, with embodiment 1, just will change into nitro iodobenzene (0.249g, 1mmol) to methoxyl group iodobenzene, and obtained target compound (III-13) 0.151g, yield is 40%.
1H?NMR(500?MHz,DMSO-d
6)δ9.63(s,1H),8.19(d,J＝9.2Hz,2H),7.85(s,1H),7.65(d,J＝9.2,2H),6.84(s,3H),3.00(s,6H).
Embodiment 50: the preparation of compound (III-14)
Operation, with embodiment 1, just will change 1-(4-iodophenyl)-benzene sulfonyl Pyrrolidine (0.334g, 1mmol) into methoxyl group iodobenzene, and obtained target compound (III-14) 0.407g, yield is 88%.
1H?NMR(500?MHz,DMSO-d
6)δ9.40(s,1H),7.77(s,2H),7.72(d,J＝8.7?Hz,2H),7.62(d,J＝8.7?Hz,2H),6.77(s,2H),3.11(t,J＝6.5?Hz,4H),2.99(s,6H),1.64(t,J＝6.5?Hz,4H).
Embodiment 51: the preparation of compound (III-15)
Operation, with embodiment 1, just will change piperidines biguanide hydrochloride (0.206g, 1mmol) into Metformin, and obtained target compound (III-15) 0.279g, yield is 76%.
1H?NMR(500?MHz,DMSO-d
6)δ8.99(s,1H),7.62(s,2H),7.29-7.36(m,4H),7.03-7.07(m,1H),6.69(s,2H),3.43(t,J＝5.2?Hz,4H),1.48-1.65(m,6H).
Embodiment 52: the preparation of compound (III-16)
Operation, with embodiment 1, just will change moroxydine hydrochloride (0.207g, 1mmol) into Metformin, and obtained target compound (III-16) 0.246g, yield is 66%.
1H?NMR(500?MHz,DMSO-d
6)δ9.13(s,1H),7.71(s,2H),7.31(d,J＝13.5?Hz,4H),7.07(s,1H),6.84(s,2H),3.63(s,4H),3.44(s,4H).
Embodiment 53: the preparation of compound (III-17)
Operation, with embodiment 1, just will change 1-phenyl biguanide hydrochloride (0.214g, 1mmol) into Metformin, and obtained target compound (III-17) 0.042g, yield is 11%.
1H?NMR(500?MHz,DMSO-d
6)δ9.51(s,2H),7.75(s,2H),7.30-7.35(m,10H),7.28(s,2H),7.11-7.14(m,2H).
Embodiment 54: the preparation of compound (III-18)
Operation, with embodiment 1, just will change pyrroles's biguanide hydrochloride (0.192g, 1mmol) into Metformin, and obtained target compound (III-18) 0.215g, yield is 60%.
1H?NMR(500?MHz,DMSO-d
6)δ8.99(s,1H),7.62(s,2H),7.29-7.36(m,4H),7.03-7.07(m,1H),6.69(s,2H),3.43(t,J＝5.2?Hz,4H),1.48-1.65(m,4H).
Embodiment 55: anti-liver cancer cell BEL-7402 biological activity test
Anti-liver cancer cell BEL-7402 activity test method: mtt assay
A principle: Thiazolyl blue (MTT) is decomposed into water-fast bluish voilet crystallization by plastosome lytic enzyme and is deposited in cell by cell, crystallisate can by dmso solution, measure its absorbance value with enzyme-linked immunosorbent assay instrument at 490nm wavelength place, indirectly reflect proliferative conditions and the number change of cell.
B cell: liver cancer cell BEL-7402 (purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences cell bank)
C experimental procedure:
1) preparation of sample: for solvable sample, every 1mg 20 μ L DMSO dissolve, and get 2uL 1000 μ L nutrient solutions and dilute, make concentration be 100 μ g/mL, then use nutrient solution serial dilution to working concentration.
2) cultivation of cell
2.1) preparation of substratum: containing 800,000 units of Penicillin in every 1000mL substratum, 1.0g Streptomycin sulphate, 10% inactivated fetal bovine serum.
2.2) cultivation of cell: by tumor cell inoculation in substratum, puts 37 DEG C, 5%CO
2cultivate in incubator, 3 ~ 5d goes down to posterity.
3) working sample is to the restraining effect of growth of tumour cell
By cell EDTA-trysinization liquid digestion, and be diluted to 1 × 10 with substratum
5/ mL, be added in 96 porocyte culture plates, every hole 100uL, puts 37 DEG C, 5%CO
2cultivate in incubator.After inoculation 24h, add the sample with substratum dilution, every hole 100 μ L, each concentration adds 3 holes, puts 37 DEG C, 5%CO
2cultivate in incubator, add the MTT of 5mg/mL after 72h in cell culture well, every hole 10 μ L, puts 37 DEG C and hatches 4h, add DMSO, every hole 150 μ L, and with oscillator vibrates, Shi Jia Za dissolves completely, by microplate reader colorimetric under 570nm wavelength.With similarity condition with containing sample, containing the culture medium culturing of same concentration DMSO cell in contrast, calculation sample is to the median lethal concentration (IC of growth of tumour cell
50), result is as shown in table 1.
With liver cancer cell BEL-7402 for model, be positive reference substance with cis-platinum, determine biguanide compound (the III-1) ~ external restraining effect to liver cancer cell growth of (III-18) 18 sample prepared in embodiment.Result shows, and in the sample that this experiment is tested, compound (III-6) has good restraining effect (the results detailed in Table 1) to experiment liver cancer cell BEL-7402 used.
The each compound of table 1 is to the IC of BEL-7402
50(ug/mL)
| Test No. | Compound | IC 50 | Test No. | Compound | IC 50 |
| 1 | (III-1) | >100 | 11 | (III-11) | 95.22 |
| 2 | (III-2) | >100 | 12 | (III-12) | >100 |
| 3 | (III-3) | >100 | 13 | (III-13) | >100 |
| 4 | (III-4) | >100 | 14 | (III-14) | >100 |
| 5 | (III-5) | >100 | 15 | (III-15) | >100 |
| 6 | (III-6) | 8.66 | 16 | (III-16) | 86.34 |
| 7 | (III-7) | 80.21 | 17 | (III-17) | 96.71 |
| 8 | (III-8) | 75.98 | 18 | (III-18) | >100 |
| 9 | (III-9) | 90.23 | 19 | Cis-platinum | 7.82 |
| 10 | (III-10) | 75.69 | ? | ? | ? |
Claims (10)
1. one kind such as formula the N-aryl biguanides hydriodate compounds shown in (III):
In formula (III): R
1, R
2respective is independently hydrogen, C1 ~ C10 alkyl or C6 ~ C10 aryl, or R
1, R
2n is between the two combined to form the heterocycle containing N or the C4 ~ C8 containing N, O; R
3represent a substituting group on hydrogen or phenyl ring, described substituting group is selected from C1 ~ C10 alkyl, C1 ~ C10 alkoxyl group, C6 ~ C10 aryl, halogen, nitrogenous electron-withdrawing substituent or alkylsulfonyl.
2. the N-aryl biguanides hydriodate compounds shown in formula (III) as claimed in claim 1, is characterized in that in described formula (III): R
1, R
2respective is independently hydrogen, methyl or phenyl, or R
1, R
2n is between the two combined to form Pyrrolidine ring, piperidine ring or morpholine ring.
3. the N-aryl biguanides hydriodate compounds shown in formula (III) as claimed in claim 1, is characterized in that in described formula (III): R
3represent a substituting group on hydrogen or phenyl ring, described substituting group is selected from methyl, methoxyl group, oxyethyl group, phenyl, cyano group, nitro, fluorine, chlorine, bromine or N-sulfonyl pyrrole acyl group.
4. the N-aryl biguanides hydriodate compounds shown in formula (III) as claimed in claim 1, is characterized in that in described formula (III): R
1, R
2respective is independently hydrogen, methyl or phenyl, or R
1, R
2n is between the two combined to form Pyrrolidine ring, piperidine ring or morpholine ring; R
3represent a substituting group on hydrogen or phenyl ring, described substituting group is selected from methyl, methoxyl group, oxyethyl group, phenyl, cyano group, nitro, fluorine, chlorine, bromine or N-sulfonyl pyrrole acyl group.
5. the preparation method of the N-aryl biguanides hydriodate compounds shown in formula (III) as claimed in claim 1, is characterized in that described preparation method is:
Being mixed with the fragrant iodo thing shown in formula (II) by biguanide hydrochloride shown in formula (I) adds in solvent, under the katalysis of metallic copper catalyzer, and under the existence of part and alkaline matter, in 60 ~ 100 DEG C of stirring reaction 2 ~ 20h, after reaction terminates, reaction solution obtains N-aryl biguanides hydriodate compounds shown in formula (III) through aftertreatment;
Described solvent is water, alcohols, ethers, sulfoxide type or nitrile; Described metallic copper catalyzer is copper halide or cuprous halide; Described part is aromatic nitrogen heterocycle, fatty nitrogen heterocyclic or amino acid; Described alkaline matter is mineral alkali or organic bases; The amount of substance of biguanide hydrochloride, metallic copper catalyzer, part, alkaline matter shown in fragrant iodo thing and formula (I) shown in described formula (II) is than being 1:0.7 ~ 1.3:0.05 ~ 0.15:0.1 ~ 0.3:3 ~ 9;
In formula (I): R
1, R
2respective is independently hydrogen, C1 ~ C10 alkyl or C6 ~ C10 aryl, or R
1, R
2n is between the two combined to form the heterocycle containing N or the C4 ~ C8 containing N, O;
In formula (II): R
3represent a substituting group on hydrogen or phenyl ring, described substituting group is selected from C1 ~ C10 alkyl, C1 ~ C10 alkoxyl group, C6 ~ C10 aryl, halogen, nitrogenous electron-withdrawing substituent or alkylsulfonyl.
6. preparation method as claimed in claim 5, is characterized in that described solvent is water, ethanol, Virahol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile, DMF or dimethyl sulfoxide (DMSO); The volumetric usage of described solvent counts 10 ~ 50mL/g with the quality of biguanide hydrochloride formula (I) Suo Shi.
7. preparation method as claimed in claim 5, is characterized in that described metallic copper catalyzer is cuprous chloride, cuprous bromide, cuprous iodide or cupric chloride.
8. preparation method as claimed in claim 5, is characterized in that described part is 2,2 '-dipyridyl, 1,10-phenanthroline, triethylene diamine, glycine, Methionin, L-glutamic acid, Gelucystine, L-Ala, aspartic acid, Threonine or α-amino-isovaleric acid.
9. preparation method as claimed in claim 5, is characterized in that described alkaline matter is salt of wormwood, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassiumphosphate or triethylamine.
10. the application of the N-aryl biguanides hydriodate compounds shown in formula (III) as described in one of Claims 1 to 4 in preparation treatment placental villi cancer drug.
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| CN111018748A (en) * | 2019-12-27 | 2020-04-17 | 广东省生物医药技术研究所 | Compound (S) -1- (1-naphthyl) ethyl biguanide and preparation method and application thereof |
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| CN103827083A (en) * | 2011-08-08 | 2014-05-28 | 韩诺生物制药株式会社 | N1-cyclic amine-N5-substituted phenyl biguanide derivatives, methods of preparing the same and pharmaceutical composition comprising the same |
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| CN111018748A (en) * | 2019-12-27 | 2020-04-17 | 广东省生物医药技术研究所 | Compound (S) -1- (1-naphthyl) ethyl biguanide and preparation method and application thereof |
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